5-gene signature (ANKRD29/CACNA2D2/DSP/HSD17B6/SPP1)

Overview

The 5-gene signature (ANKRD29/CACNA2D2/DSP/HSD17B6/SPP1) is a composite gene-expression signature used in recent biomedical research as a prognostic and tumor microenvironment–associated marker set, particularly in cancer studies. As a gene signature rather than a single gene product, it represents a coordinated expression pattern across five genes: ANKRD29, CACNA2D2, DSP, HSD17B6, and SPP1. In the studies provided, this signature was linked to tumor niche biology, immune infiltration, therapy response, and spatial compartmentalization of tumor tissues.

Among the five genes, SPP1 (secreted phosphoprotein 1) appears to be the most biologically prominent in the recent literature contexts. It has been associated with macrophage polarization, tumor progression, and immune-state remodeling, including signaling through the CD44/JAK2/STAT3 signaling pathway. The other genes in the signature were discussed mainly as part of a multigene predictive model, with CACNA2D2, DSP, HSD17B6, and ANKRD29 contributing to the signature’s ability to stratify disease states and infer tumor microenvironment dynamics.

Focus of Latest Publications

Recent publications have examined the 5-gene signature ANKRD29/CACNA2D2/DSP/HSD17B6/SPP1 primarily as a prognostic and mechanistic model in lung adenocarcinoma, especially in the context of platinum resistance and tumor microenvironment dynamics. In a multi-omics study using public datasets, spatial transcriptomics, consensus clustering, and machine learning, this signature was refined from platinum resistance-related genes and showed strong predictive performance for platinum resistance, with an AUC of 0.9639. The study also linked the signature to distinct spatial expression patterns within the tumor, including SPP1 and DSP in tumor niches, HSD17B6 and CACNA2D2 in epithelial regions, and ANKRD29 depletion in stromal areas.

Functional experiments in lung adenocarcinoma cell lines further supported the model’s biological relevance. Overexpression of ANKRD29 and CACNA2D2 sensitized A549/DDP cells to cisplatin, whereas overexpression of DSP, SPP1, and HSD17B6 promoted resistance. In nude mouse experiments, these genes were also reported to be closely related to cisplatin resistance in lung adenocarcinoma. Together, these findings suggest that the signature captures both predictive and functional aspects of platinum response.

Related studies have highlighted one component of the signature, SPP1, as a broader marker of disease progression and immune regulation. In lung cancer, enhanced SPP1 signaling was associated with a cold tumor microenvironment, reduced immune infiltration, and immunotherapy resistance, while anti-SPP1 treatment improved CD8+ T cell function, reduced M2-like macrophage polarization, and enhanced anti-PD-1 efficacy. In thyroid cancer, exosomal SPP1 was reported to promote tumor progression by driving macrophage M2 polarization through the CD44/JAK2/STAT3 signaling pathway.

SPP1 has also been implicated in other disease contexts, including MASLD progression, where it was noted among genes upregulated across disease stages, and neurodegeneration, where Spp1 was identified as a biomarker of disease-associated microglial states across disorders such as Alzheimer's disease and Parkinson's disease. Collectively, the recent literature positions the 5-gene signature as a clinically relevant biomarker set with particular value for predicting cisplatin resistance in lung adenocarcinoma, while also reflecting broader roles for SPP1 in inflammation, immune modulation, and disease progression.

Key Publications

• NEWJun Integrative Multi-Omics Analysis Elucidates the Progressive Disease Landscape and Reveals Dynamic Protein Biomarkers for MASLD Surveillance. (FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2026, PMID 42268665): "with notable upregulation of AKR1B10, COL1A2, and SPP1 and downregulation of CYP2C19."
• May Clinical significance of secreted phosphoprotein-1 overexpression in cancers. (International journal of clinical oncology, 2026, PMID 42204033): "Dysregulated SPP1 expression has been involved in the pathogenic progression of various tumors."
• May Thyroid cancer-derived exosomal SPP1 promotes tumor progression by driving macrophage M2 polarization through the CD44/JAK2/STAT3 signaling pathway. (Organogenesis, 2026, PMID 42153613): "While secreted phosphoprotein 1 (SPP1) drives macrophage M2 polarization and cancer progression in multiple malignancies, its role in thyroid cancer remains poorly understand."
• May Multi-omics profiling reveals tumor microenvironment characteristics linked to immunotherapy response and prognosis in non-small cell lung cancer. (NPJ precision oncology, 2026, PMID 42115771): "High-ZNFRS tumors exhibited a 'cold' tumor microenvironment (TME) characterized by reduced immune infiltration, immunotherapy resistance, and enhanced SPP1 signaling."
• Apr Multi-Omics reveals SPP1 + malignant and CXCR4+ TAM crosstalk predicts immunotherapy response in lung adenocarcinoma. (Discover oncology, 2026, PMID 42045760): "Multi-Omics reveals SPP1+ malignant and CXCR4+ TAM crosstalk predicts immunotherapy response in lung adenocarcinoma."
• Jun A Cross-Disease Microglial Transcriptional Program Characterizes Neurodegeneration and Highlights SPP1 as a Biomarker. (Glia, 2026, PMID 42011986): "...and highlights Spp1 as a biomarker of disease-associated microglia states."
• May Integration of Single-Cell RNA Sequencing and Machine Learning to Identify and Validate Prognostic Genes With Lymph Node Metastasis and Immune Cell Signatures in Lung Adenocarcinoma. (FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2026, PMID 41979566): "RGS20, KYNU, RAET1E, FGF12, GJB2, CACNA2D2, FURIN, and GDF10 were identified as prognostic genes with LNM."
• Apr Spatial and multi-omics transcriptomic dissects platinum resistance in lung adenocarcinoma: a five-gene predictive model with tumor microenvironment dynamics. (Chemico-biological interactions, 2026, PMID 41662930): "Spatial transcriptomics demonstrated compartmentalized expression patterns: SPP1/DSP localized to tumor niches, HSD17B6/CACNA2D2 to epithelial regions, and ANKRD29 depletion in stromal areas."